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Neuroscience and Mental Health > Pharmacological Interventions in addiction > Flashcards

Pharmacological Interventions in addiction Flashcards

1
Q

Treatment gap for mental disorders?

A

Alcohol abuse/dependence has highest gap (<10% are treated)

SCZ has lowest gap

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2
Q

Overview of methods of pharmacotherapies for addictions

A
  • substitution: give a drug to replace the abused one e.g. nicotine, opiates, BENZOS (diazepam/valium) for alcohol
  • withdrawal: treat it
  • abstinence: to prevent relapse
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3
Q

Role of alcohol with GABA receptor?

A

Drinking alcohol: activates GABA (inhibitory)

Regular drinking (not necessarily dependence): decreased GABA sensitivity]- alcohol tolerance

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4
Q

Role of alcohol with NMDA receptor?

A

Alcohol is a NMDA receptor antagonist -> reduced Ca2_ influx -> reduced excitation

ACUTE: NMDA inhibition

CHRONIC: receptor upregulation which is assoc w/ impaired memory

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5
Q

Molecular mechanisms of alcohol withdrawal?

A
  • increased NMDA acitivity and L-type Ca channel -> Ca2+ influx -> hyperexcitability and cell death
  • decreased GABA-benzo function and decreased Mg2+ inhibition via NMDA-r
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6
Q

Experimental evidence in the role of detoxes?

A

More detoxes assoc w/ less resposive treatment and heavier drinking

More detoxes assoc w/ cognitive impairment

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7
Q

Experimental evidence of glutamate and alcohol withdrawal?

A

(1)
MRS (Mag Res Spectroscopy)
day 1: increased glutamate
day 14: glutamate levels reduced closer to healthy controls

(2)
Acamprosate reduces MRS glutamate

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8
Q

Overview of treatment regimens for alcohol detox?

A
  • Benzos are efficacious in reducing symptoms and signs of withdrawal and are treatment of choice
  • -> no particular one (but consider kinetics e.g. lorazepam for liver failure
  • -> some centres add acamprosate for anti-glutamate action
  • carbamazpeine (glutamatergic anticonvuls) shown to be efficacious as an alternative to benzos]- mainly in other parts of world
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9
Q

Importance of vitamin supplementation in alcoholism?

A
  • most alcohol dependent are vitamin deficient
  • thiamine (B1) is key
  • -> involved in brain metab
  • -> adds to already toxic increased glutamate where brain cells are at risk of excitability (seizures)/death
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10
Q

Outcomes of vitamin deficiency?

A 
Wernicke's Encephalopathy
- opthalmopleiga (nystagmus)
- ataxia
- acute confusion
[but these only present in 10% of pts, so must be alert]
---> fatal in 20%; medical emergency

[can detriorate to]
Korsakoff’s Syndrome
- irreversible short-term mem loss in presence of “normal” other cogn performance

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11
Q

Specifics of thiamine administration?

A
  • IV/IM]- due to poor diet and aborption
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12
Q

DA relation to increase in substance use over time

A

EXPERIMENTAL USE

  • low levels of DRD2 assoc w/ drug liking and impulsivity
  • increase DA in substances of abuse

INCREASE -> DEPENDENCE

  • low DRD2 levels seen in stim & alc addicts]- higher DRD3 in stim addicts, but not change for alc
  • DA release is blunted or non-existent
  • can get “high” without detectable increase in DA
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13
Q

DA and pharmacotherapy for addiction?

A

Block DA-ergic function to prevent high
- D2 antag: antipsych (atypical/typical)

Boost DA-ergic function to reduce dysphoria/irritability
- DA agonists (bromocryptine, disulfiram, methylphenidate, substitute e.g. with amphetaine, bupropion (DAT reuptake block), DRD3 antag (presynaptic- negative fdbk)

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14
Q

Mechanisms of alcohol metabolismt?

A

Alcohol -alc dehydrogenase-> acetaldehyde -aldehyde dehydrogenase ALDH-> acetate

Acetaldehyde build up causes nausea/flushing/headache/vomiting/palpitations/hypotension

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15
Q

How to target alcohol metabolism?

A

Disulfiram (200mg) inhibits aldehyde dehydrogenase

Contraind: psychosis/severe liver or cardiac path/epilepsy

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16
Q

Non-targeted effects of disulfiram

A

Dopamine B hydroxylase is the same family of aldehyde dehydrogenase

DA -DA-B-Hydroxylase-> NA

Disulfiram inhibits DA-B-Hydx too -> increase DA and less NA -> anxiety/mania/psychosis/depression

17
Q

How to target GABA in alcohol dependence?

A

PHYSIOLOGY
GABA inhibits DA neurons which act on NAcc

μ-opiate-R are inhibitory for GABA -> increase DA firing

PHARMACOLOGY
- Baclofen is an agonist for GABA-B-r: shown to improve abstinence rates in alcohol dependence

  • Tiagabine, vigabatrin, gabapentin, topiramate increase GABA levels and induce a similar effect
  • opiate antag e.g. naltrexone block μ-opiate-R -> increased GABA -> reduced DA activity
18
Q

(E) of baclofen?

A

(E)- Xi & Stein
Reduces alc self-administration]- baclofen mainly use for alcohol

Same seen for heroin and cocaine self administration

19
Q

Relevance of naltrexone (ACTION ON BODY; EFFECT ON PT; MEDICAL USE)?

A

[opiate antag]

ACTION ON BODY
decreases pleasurable effects of alcohol (reduces impulsivity and modulates stress response too)

EFFECT ON PT
- reduces relapse rates to heavy drinking

USE OF NALTREXONE

  • start after detox at 50mg od
  • no opioid analgesia
  • can “safely” drink]- can reduce drinking when started whilst drinking
  • NICE: oral for 6 months; stop if drinking alc for 4-6 weeks
20
Q

Types of opiate receptor and their action

A

μ: the pleasant feeling

kappa: the negative/depressive feeling

21
Q

μ and kappa opioid receptor over stages of alcohol use (acquisition/abstinence/relapse)

A

ACQUISITION
high μ
low(er) kappa

ABSTINENCE/WITHDRAWAL
no μ
low kappa

RELAPSE
low μ
high kappa

22
Q

Relevance of nalmefene (ACTION/EFFECT/USE)?

A

ACTION
decreases pleasurable effects of alcohol

EFFECT
reduces drinking

USE

  • alc dependence (high drinking, psychosocial treatment and still drinking a lot); less severe dependence (doesnt need dtex)
  • start when drinking (18g) as eeded
  • S/E: nausea, insomnia]- severe
  • no opioid analgesia
  • recommended by NICE
23
Q

Molecular features of acamprosate and its effects?

A

Taurine derivative

Unclear pharmacology, but reduces NMDA activity
- partial agonsit at modulatory site (via AMPA and mGLUR5)

-> increases abstinence rates and decreases relapses

24
Q

How to decide which medication to give?

A

Starting post-detox

  • support abstinence: acaprosate + disulfiram
  • reduce relapse risk in “samplers”: naltrexone
  • support abstinency for those w/ prominent anxiety: baclofen

Start whilst drinking to reduce drinking:
- Nalmefene (naltrexone)

25
Q

How to “substitute” for heroin use?

A

Methadone

  • blocks “on top” heroin use
  • longer half life
  • when in brain, heroin has less effect (as receptor blockage)
26
Q

Types of opiates in pharmacotherapy?

A

Full Agonist
morphine, methadone

——–potentially lethal dose cutoff——–

Partial Agonist
buprenorphin

Antagonist
naltrexone

NB: naloxone must be available in the event of an opiate OD

27
Q

Buprenorphin mechanism of action?

A
  • High affinity for receptor, stopping “on top” heroin use]- so heroin has no effect on top
  • long half life -> prolonged cover
28
Q

OPIATES: Antagonist concept overview

A
  • no intrinsic activity, just blocks receptor to deny access for other drug

BUT

  • no reinforcement, so poor compliance
  • precipitate withdrawal
29
Q

OPIATES: Partial agonist concept overview

A

max effect: background stimulation of buprenorphine i.e. severely reduced

30
Q

Opiate maintenance treatment overview?

A

Methadone:

  • full agonist
  • risk of fatal resp depress
  • block effects of “on top” heroin

Buprenorphine

  • partial μ-agonist and kappa antag
  • no/less risk of fatal resp depres
  • block “on top” heroin effects
  • less dysphoria/feel more normal

Naltrexone]- for relapse prevention
- non-selective antag

31
Q

Opiate withdrawal symptoms?

A

Altered function in locus coeruleus (NA storm)

  • mydriasis, tachycardia, piloerection, restlessness
  • diarrhoea, sweating, rhinorrhoea
  • dysphora, insomnia, shivering

YOU DON’T NEED TO GIVE OPIATES TO TREAT OPIATE WITHDRAWAL

32
Q

Relevance of opiate maintenance treatment?

A
  • [reduce neurobiology of addiction]
  • stops street use and reduces crime
  • reduces IV risks
  • keep in healthcare (psychosocial treatment)
  • easier withdrawal when ready (flexible dosing)
33
Q

Neurobiological basis of opiate withdrawal in locus coeruleus

A

Baseline: normal NA production

Acute opioid use: abnormally low NA production

Chronic opioid use: increased converting enzyme activity -> normal NA level

Discontinuing opioid use: increase cAMP (due to loss of inhibition) -> NA excessively high

34
Q

Pharmacology of nicotine addiction

A

Nicotine replacement aids substitution, withdrawal and abstinence (i.e. relapse prevention): varenicline (partial nicotinic agonsit)

Bupropion (DA/NAergic) used for relapse prevention

NB: this must be done in addition to psychosocial smoking cessation therapies

Neuroscience and Mental Health (65 decks)

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